Chromatin remodelers are ATP-dependent DNA translocases that catalyze disassembly, reassembly, and repositioning of nucleosomes throughout eukaryotic genomes. As evidenced from multiple types of cancer and developmental disorders associated with remodeler inactivation, chromatin remodeling is essential for normal growth and development. Remodeling requires transient and controlled disruption of histone-DNA interactions, with different families of remodelers possessing unique domains thought to assist or regulate action of a conserved ATPase motor. Our crystal structure of the Chd1 chromatin remodeler provided the first view of ATPase motor regulation, showing how a DNA-binding surface of the ATPase motor was blocked by adjacent chromodomains. As seen from work with the ISWI remodeler family, the auto-inhibitory nature of the Chd1 chromodomains has proven to be a common strategy for regulating ATPase action on the nucleosome. However, it remains unclear how such domain-domain interactions enable remodelers to sense and respond to particular nucleosome substrates, or achieve unique remodeling outcomes. Here we follow up our recent discoveries of Chd1 architecture on the nucleosome, where the Chd1 DNA-binding domain was found to directly communicate with the chromo-ATPase across the gyres of the nucleosome. We propose to test the hypothesis that inter-domain interactions of Chd1 are responsible for sensing DNA outside the nucleosome and that domains work together to achieve particular remodeling outcomes. In addition to remodeler regulation, the mechanism by which chromatin remodelers reposition nucleosomes along DNA is also poorly understood. Intriguing single molecule FRET experiments with the ISWI remodeler have revealed step-like and discontinuous movements DNA, suggesting that DNA behaves as a spring on the nucleosome. We will test this idea and further investigate DNA interactions needed for high processive steps that we also observe for Chd1. Together, these studies will provide new mechanistic insights into how chromatin remodelers manipulate the structure of the nucleosome and use domain-domain communication to regulate remodeler action. !
Chromatin remodelers are the enzymes responsible for establishing and maintaining this genome packaging, acting to physically expose or bury particular DNA sequences within genes. Disruptions of chromatin remodelers have been directly linked to cancer and other human diseases, highlighting the important role of chromatin remodeling for proper cellular growth and survival. By uncovering the mechanisms by which chromatin remodelers reshape the physical packaging of the genome, we hope to better understand fundamental processes that are essential for human health.
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